Crystallographic characterisation and development of bi-substrate inhibitors of coronavirus nsp14 methyltransferase

RSC Medicinal Chemistry 2026 Open access

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Authors: Irene Georgiou, Colin Robinson, Sean N. O’Byrne, Alex Matsuda, Przemysław Grygier, Craig D. L. Smith, Sandra M. O’Neill, Shamshad A. Ahmad, Suzanne Norval, John M. Post, Mirjam G. J. Groenewold, Nadya Urakova
+15 more Patrick Wanningen, Leanid Kresik, Jacek Plewka, Adrien Delpal, Kexin See, T.C. Eadsforth, Kinga Wierzbicka, Étienne Decroly, Kumar Singh Saikatendu, Edcon Chang, Eric J. Snijder, Krzysztof Pyrć, Anna Czarna, Duncan E. Scott, Ian Hugh Gilbert
DOI: 10.1039/d5md00896d
Cited by: 0
References: 48

Abstract

= 53 nM), SARS-CoV-1, and two alphacoronaviruses, with excellent selectivity over human RNMT and flaviviral MTase. In general, the compounds demonstrated favourable metabolic stability, passive permeability, and no HepG2 cytotoxicity. However, cellular antiviral activity was limited, revealing disconnects between enzyme inhibition and phenotypic response. These findings provide a structural framework for optimizing bi-substrate methyltransferase inhibitors against coronaviruses with a view for pan-coronaviral activity.

Fields of Study & Subjects

SARS-CoV-2 and COVID-19 Research Computational Drug Discovery Methods RNA Research and Splicing

Publication details

Journal / source
RSC Medicinal Chemistry
Volume
17
Issue
2
Pages
1015–1030
Publication date
1 January 2026
Language
EN